Pages 343-354
Review
Amit Pal*, Mariacristina Siotto*, Rajendra Prasad, Rosanna Squitti (Handling Associate Editor: Roberta Ghidoni) *These authors contributed equally to this work.
Towards a Unified Vision of Copper Involvement in Alzheimer’s Disease: A Review Connecting Basic, Experimental, and Clinical Research
Abstract: Copper is an essential micronutrient for physiological cell functioning and central nervous system (CNS) development. Indeed, it is a cofactor of many proteins and enzymes in a number of molecular pathways, including energy generation, oxygen transportation, hematopoiesis, cellular growth and metabolism, and signal transduction. This is because it serves as a catalyst of reduction-oxidation (redox) reactions in these processes. When copper is kept under control, bound to special proteins, it yields key properties. However, when it spirals out of control, it is exchanged among small compounds (it is loosely bound to them), and its redox activity makes it dangerous for cell viability, promoting oxidative stress. Copper homeostasis in the CNS is securely synchronized, and perturbations in brain copper levels are known to underlie the pathoetiology of wide a spectrum of common neurodegenerative disorders, including Alzheimer’s disease. The main objective of this review is to provide some of the most relevant evidence gleaned from recent studies conducted on animal models and humans, and to discuss the evidence as it pertains to a new concept: Aberrant copper metabolism, which appears to have a genetic basis, is a modifiable risk factor accelerating Alzheimer’s disease and initiation/progression of cognitive deficits in a percentage of susceptible persons.
Pages 355-373
Review
Jonathan Stone, Daniel M. Johnstone, John Mitrofanis, Michael O’Rourke
The Mechanical Cause of Age-Related Dementia (Alzheimer’s Disease): The Brain is Destroyed by the Pulse
Abstract: This review traces evidence that age-related dementia (Alzheimer’s disease) results from the destructive impact of the pulse on cerebral vasculature. Evidence is reviewed that the neuropathology of the dementia is caused by the breakdown of small cerebral vessels (silent microbleeds), that the microbleeds result from pulse-induced damage to the cerebral vessels, and that pulse becomes increasingly destructive with age, because of the age-related stiffening of the aorta and great arteries, which causes an increase in the intensity of the pressure pulse. Implications for therapy are discussed, and evidence is reviewed that pulse-induced destruction of the brain, and of another highly vascular organ, the kidney, are becoming the default forms of death, the way we die if we survive the infections, cardiovascular disease, and malignancies, which still, for a decreasing minority, inflict the tragedy of early death.
Pages 375-378
Short Communication
Cheng Zhang, Robert A. Rissman, June Feng (Handling Associate Editor: Xuemin Xu)
Characterization of ATP Alternations in an Alzheimer’s Disease Transgenic Mouse Model
Abstract: Mitochondrial impairment as evidenced by decline in adenosine 5’-triphosphate (ATP) is associated with oxidative stress in Alzheimer’s disease neuropathology and suggests that mitochondria may fail to maintain cellular energy, through reduced ATP production in neurons. To gain insights into the ATP characteristics of Alzheimer’s disease transgenic (Tg) mice, we investigated ATP contents in the brain and whole blood of Tg mice at three ages (1-, 5-, and 24-months old). Overall, our results demonstrate that tissue ATP contents in Tg mice are significantly reduced, suggesting a decrease of tissue ATP production and mitochondrial dysfunction.
Pages 379-383
Short Communication
Rachel H.L.H. Rueli, Arlene C. Parubrub, Andrea S. T. Dewing, Ann C. Hashimoto, Miyoko T. Bellinger, Edwin J. Weeber, Jane H. Uyehara-Lock, Lon R. White, Marla J. Berry, Frederick P. Bellinger
Increased Selenoprotein P in Choroid Plexus and Cerebrospinal Fluid in Alzheimer’s Disease Brain
Abstract: Subjects with Alzheimer’s disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium.
Pages 385-396
Jun Wang, Lan Tan, Hui-Fu Wang, Chen-Chen Tan, Xiang-Fei Meng, Chong Wang, Shao-Wen Tang, Jin-Tai Yu (Handling Associate Editor: Francesco Panza)
Anti-Inflammatory Drugs and Risk of Alzheimer’s Disease: An Updated Systematic Review and Meta-Analysis
Abstract: Background: In the past 20 years, substantial evidence from laboratory and epidemiologic studies have suggested that anti-inflammatory medications could defer or prevent the occurrence of Alzheimer’s disease (AD). However, several studies do not corroborate these findings. Objective: To evaluate the association of anti-inflammatory drug use on the incidence of AD. Methods: Pubmed, Embase, and Cochrane Library databases were searched up to March 2014. Studies evaluating the association between use of anti-inflammatory drugs and AD risk were included. Relative risks (RRs) with 95% confidence intervals (CIs) were meta-analyzed using random effects models and were grouped by anti-inflammatory type and duration of drug use. Results: In observational studies, use of non-steroidal anti-inflammatory drugs (NSAIDs) was significantly associated with a reduced risk of AD (RR, 0.72; 95%CI, 0.62-0.84) compared to no use of NSAIDs, especially in long term users (RR, 0.36; 95%CI, 0.17-0.74); the risks of AD were also lower in both aspirin (RR, 0.77; 95%CI, 0.63-0.95) and non-aspirin NSAID users (RR, 0.65; 95%CI, 0.47-0.88) compared with nonusers; whereas the use of corticosteroids showed no significant association (RR, 0.62; 95%CI, 0.26-1.46). In the single randomized controlled trial (RCT), NSAID use showed no significant effect on AD risk among dementia-free individuals (p>0.05). Conclusion: Observational studies support the use of NSAIDs for prevention of AD, but RCT do not. Well-designed studies and innovative approaches are required to illuminate the exact relationship between NSAID use and AD risk. The appropriate dosage and duration of use to benefit and the safety are also needed to determine.
Pages 397-408
George Stothart, Nina Kazanina, Risto Näätänen, Judy Haworth, Andrea Tales (Handling Associate Editor: Charles Duffy)
Early Visual Evoked Potentials and Mismatch Negativity in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Cortical visual association areas are highly vulnerable to Alzheimer’s disease (AD) microscopic pathology. Visual evoked potentials (VEPs) provide the tools to examine the functional integrity of these areas and may provide useful indicators of early disease progression. Objective: To assess the functional integrity of visual association area processing in AD and amnestic mild cognitive impairment (aMCI) using VEPs. Methods: We investigated the visual processing of healthy older adults (n=26), AD (n=20), and aMCI (n=25) patients in a visual oddball paradigm designed to elicit the visual P1, N1, and visual mismatch negativity (vMMN). Results: AD patients showed a significant reduction of P1 and N1 VEP amplitudes and aMCI patients showed a reduction in N1 amplitude compared to healthy older adults. P1 amplitude in response to deviant stimuli and vMMN amplitude were found to be associated with the degree of cognitive impairment as measured by the Mini-Mental State Examination. Conclusions: Changes in VEPs in AD may be a consequence of the microscopic AD pathology typically found in the extrastriate cortex. Neural measures of visual processing may help to better characterize subgroups of aMCI patients likely to develop AD. Additionally, VEPs and vMMN may provide objective markers of cognitive decline.
Pages 409-423
Akihiro Matsumura, Syuuichirou Suzuki, Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Hiromi Suzuki, Ayano Yamauchi, Kazuyuki Takata, Yoshihisa Kitamura, Shun Shimohama
Temporal Changes of CD68 and α7 Nicotinic Acetylcholine Receptor Expression in Microglia in Alzheimer’s Disease-Like Mouse Models
Abstract: We previously reported that activated microglia are involved in amyloid-β (Aβ) clearance and that stimulation of α7 nicotinic acetylcholine receptors (nAChR) in microglia enhances Aβ clearance. Nevertheless, how microglia and α7 nAChR in microglia are affected in Alzheimer’s disease (AD) remains unknown. The present study aimed to collect fundamental data for considering whether microglia are potential targets for AD treatment and the appropriate timing of therapeutic intervention, by evaluating the temporal changes of Aβ, microglia, neurons, presynapses, and α7 nAChR by immunohistochemical studies in mouse models of AD. In an Aβ-injected AD mouse model, we observed early accumulation of CD68-positive microglia at Aβ deposition sites and gradual reduction of Aβ. Microglia were closely associated with Aβ deposits, and were confirmed to participate in clearing Aβ. In a transgenic mouse model of AD, we observed an increase in Aβ deposition from 6 months of age, followed by a gradual increase in microglial accumulation at Aβ deposit sites. Activated microglia in APdE9 mice showed two-step transition: a CD68-negative activated form at 6-9 months and a CD68-positive form from 12 months of age. In addition, α7 nAChR in microglia increased markedly at 6 months of age when activated microglia appeared for the first time, and decreased gradually coinciding with the increase of Aβ deposition. These findings suggest that early microglial activation is associated with α7 nAChR upregulation in microglia in APdE9 mice. These novel findings are important for the development of new therapeutic strategy for AD.
Pages 425-430
Jocelyn Charles, Gary Naglie, Jacques Lee, Rahim Moineddin, Susan Jaglal, Mary C. Tierney
Self-Report Measures of Well-Being Predict Incident Harm Due to Self-Neglect in Cognitively Impaired Seniors Who Live Alone
Abstract: Background: Primary care physicians (PCPs) increasingly must identify which of their cognitively impaired patients who live alone are at greatest risk of harm due to self-neglect. Objectives: To determine whether brief patient self-report measures could accurately do this. Methods: Participants were ≥ 65 years, lived alone, and recruited from PCPs’ practices, community agencies, a hospital emergency department, and acute care medical units. All had cognitive impairment (≤130 on the Dementia Rating Scale) and all had a PCP. Baseline self-report measures included: Geriatric Depression Scale (GDS), a social resources scale, a single item health rating scale, and the Quality of Life Alzheimer’s Disease Scale. We adjusted for baseline demographic, health, and mental status differences. We prospectively captured incidents of harm involving self-neglect or disorientation, resulting in physical injury, property loss, or damage, and requiring emergency services. These were obtained over a one-year longitudinal period, at 3-month intervals, from PCPs and caregivers. Emergency service records were obtained and reviewed for each incident. Proportional hazards modeling estimated how well the self-report measures predicted time to the first incident harm. Results: 190 women and 34 men were followed. Based on the agreement of three medical raters, 23 participants (10%) experienced harmful outcomes. Being depressed on the GDS and rating one’s health as fair or poor were the only two measures that significantly shortened time to first harmful outcome. Conclusion: GDS and self-rated health are simple measures to administer in the primary care setting and may be useful to PCPs in the earlier identification of those at greatest risk of harm in this vulnerable group of patients.
Pages 431-437
Nur-Ezan Mohamed, Jasinda H. Lee, Paul T. Francis, Margaret M. Esiri, Christopher P. Chen, Mitchell K.P. Lai
Differential Alterations of Neocortical GluN Receptor Subunits in Patients with Mixed Subcortical Ischemic Vascular Dementia and Alzheimer’s Disease
Abstract: Background: Glutamatergic deficits are well-established neurochemical findings in Alzheimer’s disease (AD) and are thought to underlie both cognitive and behavioral symptoms of the disease. However, it is unclear whether subcortical ischemic vascular dementia (SIVD) and mixed SIVD/AD (MixD) manifest similar changes in the glutamatergic system. Objective: To measure the immunoreactivities of NMDA receptor GluN1, GluN2A, and GluN2B subunits in SIVD and MixD. Methods: Postmortem neocortical tissues from a cohort of well-characterized, longitudinally followed-up patients with SIVD and MixD, together with age-matched controls, were processed for immunoblotting with GluN subunit-specific antibodies. Results: There was a significant reduction of GluN1 only in MixD, while significant increases of GluN2A and GluN2B were found only in SIVD. Furthermore, GluN1 loss and GluN2A/2B upregulation was associated respectively with higher Braak stages and lacunar infarct scores. Conclusions: Our data suggest that the differential alterations of GluN subunits in SIVD and MixD may result from separate, interacting disease processes, and point to the potential utility of glutamatergic approaches for pharmacotherapy.
Pages 439-453
Christoph Berger, Anna-Katharina Erbe, Inga Ehlers, Ivo Marx, Karlheinz Hauenstein, Stefan Teipel
Effects of Task-Irrelevant Emotional Stimuli on Working Memory Processes in Mild Cognitive Impairment
Abstract: Background: Research suggests generally impaired cognitive control functions in working memory (WM) processes in amnestic mild cognitive impairment (MCI) and incipient Alzheimer’s disease (AD). Little is known how emotional salience of task-irrelevant stimuli may modulate cognitive control of WM performance and neurofunctional activation in MCI and AD individuals. Objective: We investigated the impact of emotional task-irrelevant visual stimuli on cortical activation during verbal WM. Methods: Twelve AD/MCI individuals and 12 age-matched healthy individuals performed a verbal WM (nback-) task with task-irrelevant emotionally neutral and emotionally negative background pictures during fMRI measurement. Results: AD/MCI individuals showed decreased WM performance compared with controls; both AD/MCI and control groups reacted slower during presentation of negative pictures, regardless of WM difficulty. The AD/MCI group showed increased activation in the left hemispheric prefrontal network, higher amygdala and less cerebellar activation with increasing WM task difficulty compared to healthy controls. Correlation analysis between neurofunctional activation and WM performance revealed a negative correlation between task sensitivity and activation in the dorsal anterior cingulum for the healthy controls but not for the AD/MCI group. Conclusion: Our data suggest compensatory activation in prefrontal cortex and amygdala, but also dysfunctional inhibition of distracting information in the AD/MCI group during higher WM task difficulty. Additionally, attentional processes affecting the correlation between WM performance and neurofunctional activation seem to be different between incipient AD and healthy aging.
Pages 455-469
Jun Yu*, Xiaobin Luo*, Hua Xu, Quan Ma, Jianhui Yuan, Xuling Li, Raymond Chuen-Chung Chang, Zhongsen Qu, Xinfeng Huang, Zhixiong Zhuang, Jianjun Liu, Xifei Yang (Handling Associate Editor: Jianzhi Wang) *These authors contributed equally to this work.
Identification of the Key Molecules Involved in Chronic Copper Exposure-Aggravated Memory Impairment in Transgenic Mice of Alzheimer’s Disease Using Proteomic Analysis
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by a progressive impairment of cognitive functions including spatial learning and memory. Excess copper exposure accelerates the development of AD; however, the potential mechanisms by which copper exacerbates the symptoms of AD remain unknown. In this study, we explored the effects of chronic copper exposure on cognitive function by treating 6 month-old triple AD transgenic (3xTg-AD) mice with 250 ppm copper sulfate in drinking water for 6 months, and identified several potential key molecules involved in the effects of chronic copper exposure on memory by proteomic analysis. The behavioral test showed that chronic copper exposure aggravated memory impairment of 3xTg-AD mice. Two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry revealed a total of 44 differentially expressed proteins (18 upregulated and 26 down-regulated) in hippocampus between the wild-type (WT) mice and non-exposed 3xTg-AD mice. A total of 40 differentially expressed proteins were revealed (20 upregulated and 20 down-regulated) in hippocampus between copper exposed and non-exposed 3xTg-AD mice. Among these differentially expressed proteins, complexin-1 and complexin-2, two memory associated proteins, were significantly decreased in hippocampus of 3xTg-AD mice compared with the WT mice. Furthermore, the expression of these two proteins was further down-regulated in 3xTg-AD mice when exposed to copper. The abnormal expression of complexin-1 and complexin-2 identified by proteomic analysis was verified by western blot analysis. Taken together, our data showed that chronic copper exposure accelerated memory impairment and altered the expression of proteins in hippocampus in 3xTg-AD mice. The functional analysis on the differentially expressed proteins suggested that complexin-1 and complexin-2 may be the key molecules involved in chronic copper exposure-aggravated memory impairment in AD.
Pages 471-480
Marcel G.M. Olde Rikkert, Frans R. Verhey, Rafael Blesa, Christine A.F. von Arnim, Anke Bongers, John Harrison, John Sijben, Elio Scarpini, Maurits F.J. Vandewoude, Bruno Vellas, Renger Witkamp, Patrick J.G.H. Kamphuis, Philip Scheltens (Handling Associate Editor: Thomas Shea)
Tolerability and Safety of Souvenaid in Patients with Mild Alzheimer’s Disease: Results of Multi-Center, 24-Week, Open-Label Extension Study
AbstractBackground. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to improve synapse formation and function in patients with Alzheimer’s disease (AD). Two double-blind randomized controlled trials (RCT) with Souvenaid of 12 and 24 week duration (Souvenir I and Souvenir II) showed that memory performance was improved in drug-naïve mild AD patients, whereas no effects on cognition were observed in a 24-week RCT (S-Connect) in mild to moderate AD patients using AD medication. Souvenaid was well-tolerated in all RCTs. Objective. In this 24-week open-label extension (OLE) study to the 24-week Souvenir II RCT, long-term safety and intake adherence of the medical food Souvenaid was evaluated. Methods. Patients with mild AD (n=201) received Souvenaid once-daily during the OLE. Main outcome parameters were safety and product intake adherence. The memory domain z-score from a revised neuropsychological test battery was continued as exploratory parameter. Results. Compared to the RCT, a similar (low) incidence and type of adverse events was observed, being mainly (68.3%) of mild intensity. Pooled data (RCT and OLE) showed that 48-week use of Souvenaid was well tolerated with high intake adherence (96.1%). Furthermore, a significant increase in the exploratory memory outcome was observed in both the active-active and control-active groups during Souvenaid intervention. Conclusion. Souvenaid use for up to 48-weeks was well tolerated with a favorable safety profile and high intake adherence. The findings in this OLE study warrant further investigation toward the long-term safety and efficacy of Souvenaid in a well-controlled, double-blind RCT.
Pages 481-492
Sarah E. MacPherson, Mario A. Parra, Sonia Moreno, Francisco Lopera, Sergio Della Sala (Handling Associate Editor: J. Wesson Ashford)
Dual Memory Task Impairment in E280A Presenilin-1 Mutation Carriers
Abstract: Patients with sporadic Alzheimer’s disease (AD) are impaired in their ability to perform two tasks concurrently compared to healthy younger and older adults, despite being able to successfully perform the tasks on their own reasonably well. Dual task impairments have also been found in those individuals with an E280A presenilin-1 genetic mutation but who do not yet meet the criteria for AD. The aim of the current study is to determine whether this dual task deficit is specific to the given combination of tasks performed simultaneously or whether it reflects a general deficit in the ability to coordinate two tasks. Thirty-one carriers of the gene mutation who did not meet the criteria for AD and 38 non-carriers were asked to perform two memory tasks simultaneously. The familial AD carriers showed significant dual task decrements compared to those family members without the gene mutation. The findings support the notion that a deficit in the mechanism responsible for coordinating the performance of two tasks may be a clinical marker for the early detection of AD due to the E280A presenilin-1 gene mutation.
Pages 493-505
Pablo Cuesta, Pilar Garcés, Nazareth P. Castellanos, Maria Eugenia López, Sara Aurtenetxe, Ricardo Bajo, José Pineda, Ricardo Bruña, Antonio García Marín, Marisa Delgado, Ana Barabash, Inés Ancín, Jose Antonio Cabranes, Alberto Fernandez, Francisco del Pozoa, Miguel Sancho, Alberto Marcos, Akinori Nakamura, Fernando Maestú (Handling Associate Editor: Susana Cid Fernández)
Influence of the APOE ε4 Allele and Mild Cognitive Impairment Diagnosis in the Disruption of the MEG Resting State Functional Connectivity in Sources Space
Abstract: The apolipoprotein E (APOE) ε4 allele constitutes the major genetic risk for the development of late onset Alzheimer’s disease (AD). However, its influence on the neurodegeneration that occurs in early AD remains unresolved. In this study, the resting state magnetoencephalography (MEG) recordings were obtained from 27 aged healthy controls and 36 mild cognitive impairment (MCI) patients. All participants were divided into carriers and non-carriers of the ε4 allele. We have calculated the functional connectivity (FC) in the source space along brain regions estimated using the Harvard-Oxford atlas and in the classical bands. Then, a two way ANOVA analysis (diagnosis and APOE) was performed in each frequency band. The diagnosis effect consisted of a diminished FC within the high frequency bands in the MCI patients, affecting medial temporal and parietal regions. The APOE effect produced a decreased long range FC in delta band in ɛ4 carriers. Finally, the interaction effect showed that the FC pattern of the right frontal-temporal region could be reflecting a compensatory/disruption process within the ɛ4 allele carriers. Several of these results correlated with cognitive decline and neuropsychological performance. The present study characterizes how the APOE ε4 allele and MCI status affect the brain’s functional organization by analyzing the FC patterns in MEG resting state in the sources space. Therefore a combination of genetic, neuropsychological, and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration.
Pages 507-524
Johann Meunier, Nozha Borjini, Cyril Gillis, Vanessa Villard, Tangui Maurice (Handling Associate Editor: Luc Buee)
Brain Toxicity and Inflammation Induced in vivo in Mice by the Amyloid-β Forty-Two Inducer Aftin-4, a Roscovitine Derivative
Abstract: Aftins (amyloid forty-two inducers) represent a novel class of tri-substituted purines derived from roscovitine, able to promote the generation of amyloid-β (Aβ)1-42 from amyloid-β protein precursor through γ-secretase activation in cell cultures. We here examined whether aftin-4 could provoke an amyloid-like toxicity in vivo in mice. The intracerebroventricular administration of aftin-4 (3-20 nmol) increased Aβ1-42, but not Aβ1-40, content in the mouse hippocampus, between 5 and 14 days after injection. Aftin-4 injection increased lipid peroxidation levels in the hippocampus, an index of oxidative stress. It increased brain contents in pro-inflammatory cytokines, IL-1β, IL-6, and TNFα, and GFAP immunolabeling, showing astrocytic reaction. Expression of the synaptic marker synaptophysin was decreased by aftin-4. Finally, the treatment provoked marked learning deficits, observed using different memory procedures: spontaneous alternation in the Y-maze, place learning in the water-maze, and passive avoidance response. The systemic intraperitoneal injection of aftin-4 in the 3-30 mg/kg dose range also induced oxidative stress and learning deficits. All these alterations could be blocked by pre-treatment with the γ-secretase inhibitor BMS-299,897, confirming that the mechanism of action of aftin-4 involves secretase activity. Furthermore, we examined if the cholinesterase inhibitor donepezil and the non-steroidal anti-inflammatory drug ibuprofen could prevent aftin-4-induced memory impairments, cytokine release, and lipid peroxidation. Donepezil prevented all alterations, whereas ibuprofen prevented the increases in cytokine release and lipid peroxidation, but only marginally the memory impairments. As a whole, this study showed that in vivo injection of aftin-4 results in a rapid, acute Alzheimer’s disease-like toxicity in the rodent brain.
Pages 525-539
Jeffrey L. Seeburger*, Daniel J. Holder*, Marc Combrinck, Catharine Joachim, Omar Laterza, Michael Tanen, Aimee Dallob, Derek Chappell, Karen Snyder, Mary Flynn, Adam Simon, Vijay Modur, William Potter, Gordon Wilcock, Mary J. Savage, A. David Smith (Handling Associate Editor: Erik Portelius) *These authors contributed equally to this work.
Cerebrospinal Fluid Biomarkers Distinguish Postmortem Confirmed Alzheimer’s Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort
Abstract: Cerebrospinal fluid (CSF) amyloid β (Aβ) and tau have been studied as markers of Alzheimer’s disease (AD). Combined Aβ42 and t tau distinguishes AD from healthy controls with a sensitivity and specificity (sens/spec) near 89% across studies. This study examined these markers in the homogeneous OPTIMA cohort, using extensive longitudinal follow up and postmortem evaluation to confirm clinicopathological status. Baseline CSF was analyzed from 227 participants with AD (97% autopsy-confirmed), mild cognitive impairment (MCI; 73% confirmed), other dementia syndrome (ODS; 100% confirmed), and controls (CTL; 27% confirmed, follow up ~9 13 years). Biomarker concentrations were analyzed using validated ELISAs. AD patients had lower CSF Aβ42 and higher t tau, p tau, t tau/Aβ42, and t tau/Aβ40 compared to CTLs, with MCI intermediate. CTL and MCI participants who progressed to AD demonstrated more AD-like profiles. Aβ40, sAβPPα, and sAβPPβ were lower in AD compared to CTL. High-level discriminators of AD from CTL were t tau/Aβ40 (AUROC 0.986, sens/spec of 92%/94%), p tau/Aβ42 (AUROC 0.972, sens/spec of 94%/90%), and Aβ42 (AUROC 0.941, sens/spec of 88%). For discriminating AD from ODS, p tau/Aβ42 demonstrated sens/spec of 88%/100% (95%/86% at the AD versus CTL cutoff) and Aβ42 demonstrated sens/spec of 84%/100% (88%/100% at the AD versus CTL cutoff). In a well-characterized, homogeneous population, a single cutoff for baseline CSF Aβ and tau markers can distinguish AD with a high level of sens/spec compared to other studies. It may be important to characterize sources of demographic and biological variability to support the effective use of CSF diagnostic assays in the broader AD population.
Pages 541-547
Olivier Piguet, Cristian E. Leyton, Liam D. Gleeson, Chris Hoon, John R. Hodges (Handling Associate Editor: Ricardo Allegri)
Memory and Emotion Processing Performance Contributes to the Diagnosis of Non-Semantic Primary Progressive Aphasia Syndromes
Abstract: Background: The two non-semantic variants of primary progressive aphasia (PPA), nonfluent/agrammatic PPA (nfv-PPA) and logopenic variant PPA (lv-PPA), share language features despite their different underlying pathology, and may be difficult to distinguish for non-language experts. Objective: To improve diagnostic accuracy of nfv-PPA and lv-PPA using tasks measuring non-language cognition and emotion processing. Methods: Thirty-eight dementia patients meeting diagnostic criteria for PPA (nfv-PPA 20, lv-PPA 18) and 21 matched healthy Controls underwent a comprehensive assessment of cognition and emotion processing, as well as a high-resolution structural MRI and a PiB-PET scan, a putative biomarker of Alzheimer’s disease. Task performances were compared between the groups and those found to differ significantly were entered into a logistic regression analysis. Results: Analyses revealed a double dissociation between nfv-PPA and lv-PPA. nfv-PPA exhibited significant emotion processing disturbance compared to lv-PPA and Controls. In contrast, only the lv-PPA group was significantly impaired on tasks of episodic memory. Logistic regression analyses showed that 87% of patients were correctly classified using emotion processing and episodic memory composite scores, together with a measure of visuospatial ability. Conclusions: Non-language presenting features can help differentiate between the two non-semantic PPA syndromes, with a double dissociation observed on tasks of episodic memory and emotion processing. Based on performance on these tasks, we propose a decision tree as a complementary method to differentiate between the two non-semantic variants. These findings have important clinical implications, with identification of patients who may potentially benefit existing therapeutic interventions currently available for Alzheimer’s disease.
Pages 549-560
Richard L. Bowen, George Perry, Chengjie Xiong, Mark A. Smith, Craig S. Atwood (Handling Editor: Massimo Tabaton)
A Clinical Study of Lupron Depot in the Treatment of Women with Alzheimer’s Disease: Preservation of Cognitive Function in Patients Taking an Acetylcholinesterase Inhibitor and Treated with High Dose Lupron Over 48 Weeks
Abstract: To test the efficacy and safety of leuprolide acetate (Lupron Depot®) in the treatment of Alzheimer’s disease (AD), we conducted a 48-week, double-blind, placebo-controlled, dose-ranging study in women aged 65 years or older with mild to moderate AD. A total of 109 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 24 inclusive were randomized to low dose Lupron Depot® (11.25 mg leuprolide acetate), high dose Lupron Depot® (22.5 mg leuprolide acetate), or placebo injections every 12 weeks. There were no statistically significant differences in primary efficacy parameters (ADAS-Cog and ADCS-CGIC), although there was a non-statistically significant trend in favor of the high dose Lupron group on the ADAS-Cog. There were no statistically significant differences in secondary efficacy parameters (NPI, ADCS-ADL, BI, and ADCS-Severity Rating). However, in the a priori designated subgroup analysis of patients taking an acetylcholinesterase inhibitor (AChEI), there was a statistically significant benefit in the high dose group compared to both the low dose and placebo groups as determined by ADAS-Cog (mean decline: 0.18, 4.21, and 3.30), ADCS-CGIC (% subjects experiencing decline: 38, 82, and 63), and ADCS-ADL (mean decline: -0.54, -8.00, and -6.85), respectively. No differences between treatment groups were seen on the NPI, ADCS-CGI Severity Rating, or the BI in the subgroup analysis. These data indicate that cognitive function is preserved in patients treated with high dose Lupron who were already using AChEIs. The positive interaction between Lupron and AChEIs warrants further investigation for the treatment of AD.
Pages 561-572
Jennifer M. Walker, Diana Klakotskaia, Deepa Ajit, Gary A. Weisman, W. Gibson Wood, Grace Y. Sun, Peter Serfozo, Agnes Simonyi, Todd R. Schachtman (Handling Associate Editor: Susan Farr) Beneficial Effects of Dietary EGCG and Voluntary Exercise on Behavior in an Alzheimer’s Disease Mouse Model
Abstract: Alzheimer’s disease (AD) is a progressive, age-dependent neurodegenerative disorder affecting specific brain regions that control memory and cognitive functions. Epidemiological studies suggest that exercise and dietary antioxidants are beneficial in reducing AD risk. To date, botanical flavonoids are consistently associated with the prevention of age-related diseases. The present study investigated the effects of 4 months of wheel running exercise, initiated at 2-months of age, in conjunction with the effects of the green tea catechin (-)-epigallocatechin-3-gallate (EGCG) administered orally in the drinking water (50 mg/kg daily) on: 1) behavioral measures: learning and memory performance in the Barnes maze, nest building, open-field, anxiety in the light-dark box; and 2) soluble amyloid-β (Aβ) levels in the cortex and hippocampus in TgCRND8 (Tg) mice. Untreated Tg mice showed hyperactivity, relatively poor nest building behaviors, and deficits in spatial learning in the Barnes maze. Both EGCG and voluntary exercise, separately and in combination, were able to attenuate nest building and Barnes maze performance deficits. Additionally, these interventions lowered soluble Aβ1-42 levels in the cortex and hippocampus. These results, together with epidemiological and clinical studies in humans, suggest that dietary polyphenols and exercise may have beneficial effects on brain health and slow the progression of AD.
Pages 573-584
Chau-Ren Jung, Yu-Ting Lin, Bing-Fang Hwang
Ozone, Particulate Matter, and Newly Diagnosed Alzheimer’s Disease: A Population-Based Cohort Study in Taiwan
Abstract: Several studies with animal research associate air pollution in Alzheimer's disease (AD) neuropathology, but the actual impact of air pollution on the risk of AD is unknown. Here, this study investigates the association between long-term exposure to ozone (O3) and particulate matter (PM) with an aerodynamic diameter equal to or less than 2.5 μm (PM2.5), and newly diagnosed AD in Taiwan. We conducted a cohort study of 95,690 individuals’ age ≥ 65 during 2001–2010. We obtained PM10 and O3 data from Taiwan Environmental Protection Agency during 2000–2010. Since PM2.5 data is only accessible entirely after 2006, we used the mean ratio between PM2.5 and PM10 during 2006–2010 (0.57) to estimate the PM2.5 concentrations from 2000 to 2005. A Cox proportional hazards model was used to evaluate the associations between O3 and PM2.5 at baseline and changes of O3 and PM2.5 during the follow-up period and AD. The adjusted HR for AD was weakly associated with a raised concentration in O3 at baseline per increase of 9.63 ppb (adjusted HR 1.06, 95% confidence interval (CI) 1.00–1.12). Further, we estimated a 211% risk of increase of AD per increase of 10.91 ppb in O3 over the follow-up period (95% CI 2.92–3.33). We found a 138% risk of increase of AD per increase of 4.34 μg/m3 in PM2.5 over the follow-up period (95% CI 2.21–2.56). These findings suggest long-term exposure to O3 and PM2.5 above the current US EPA standards are associated with increased the risk of AD.
Pages 585-598
Milap A. Nowrangi, Ozioma Okonkwo, Constantine Lyketsos, Kenichi Oishi, Susumu Mori, Marilyn Albert, Michelle M. Mielke (Handling Associate Editor: David Zhu)
Atlas-Based Diffusion Tensor Imaging Correlates of Executive Function
Abstract: Impairment in executive function (EF) is commonly found in Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Atlas-based diffusion tensor imaging (DTI) methods may be useful in relating regional integrity to EF measures in MCI and AD. 66 participants (25 normal controls, 22 MCI, and 19 AD) received DTI scans and clinical evaluation. DTI scans were applied to a pre-segmented atlas and fractional anisotropy (FA) and mean diffusivity (MD) were calculated. ANOVA was used to assess group differences in frontal, parietal, and cerebellar regions. For regions differing between groups (p<0.01), linear regression examined the relationship between EF scores and regional FA and MD. Anisotropy and diffusivity in frontal and parietal lobe white matter structures were associated with EF scores in MCI and only frontal lobe structures in AD. EF was more strongly associated with FA than MD. The relationship between EF and anisotropy and diffusivity was strongest in MCI. These results suggest that regional white matter integrity is compromised in MCI and AD and that FA may be a better correlate of EF than MD.
Pages 599-611
Xiaoying Tang, Dominic Holland, Anders M. Dale, Laurent Younes, Michael I. Miller, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Babak Ardekani) Baseline Shape Diffeomorphometry Patterns of Subcortical and Ventricular Structures in Predicting Conversion of Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: In this paper, we propose a novel predictor for the conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD). This predictor is based on the shape diffeomorphometry patterns of subcortical and ventricular structures (left and right amygdala, hippocampus, thalamus, caudate, putamen, globus pallidus, and lateral ventricle) of 607 baseline scans from the Alzheimer’s Disease Neuroimaging Initiative database, including a total of 210 healthy control subjects, 222 MCI subjects, and 175 AD subjects. The optimal predictor is obtained via a feature selection procedure applied to all of the 14 sets of shape features via linear discriminant analysis, resulting in a combination of the shape diffeomorphometry patterns of the left hippocampus, the left lateral ventricle, the right thalamus, the right caudate, and the bilateral putamen. Via 10-fold cross-validation, we substantiate our method by successfully differentiating 77.04% (104/135) of the MCI subjects who converted to AD within 36 months and 71.26% (62/87) of the non-converters. To be specific, for the MCI-converters, we are capable of correctly predicting 82.35% (14/17) of subjects converting in 6 months, 77.5% (31/40) of subjects converting in 12 months, 74.07% (20/27) of subjects converting in 18 months, 78.13% (25/32) of subjects converting in 24 months, and 73.68% (14/19) of subject converting in 36 months. Statistically significant correlation maps were observed between the shape diffeomorphometry features of each of the 14 structures, especially the bilateral amygdala, hippocampus, lateral ventricle, and two neuropsychological test scores—the Alzheimer's Disease Assessment Scale-Cognitive Behavior Section and the Mini-Mental State Examination.
Pages 613-624
Christian Barucker, Anette Sommer, Georg Beckmann, Murat Eravci, Anja Harmeier, Carola G. Schipke, Damian Brockschnieder, Thomas Dyrks, Veit Althoff, Paul E. Fraser, Lili-Naz Hazrati, Peter St George-Hyslop,, John C.S. Breitner, Oliver Peters, Gerhard Multhaup
Alzheimer Amyloid Peptide Aβ42 Regulates Gene Expression of Transcription and Growth Factors
Abstract: The pathogenesis of Alzheimer disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
Pages 625-633
Simone C. Egli, Daniela I. Hirni, Kirsten I. Taylor, Manfred Berres, Axel Regeniter, Achim Gass, Andreas U. Monsch, Marc Sollberger (Handling Associate Editor: Ben Schmand)
Varying Strength of Cognitive Markers and Biomarkers to Predict Conversion and Cognitive Decline in an Early-Stage-Enriched Mild Cognitive Impairment Sample
Abstract: Background: Several cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers predict conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia. However, predictors might be more or less powerful depending on the characteristics of the MCI sample. Objective: To investigate which cognitive markers and biomarkers predict conversion to AD dementia and course of cognitive functioning in a MCI sample with a high proportion of early-stage MCI patients. Methods: Variables known to predict progression in MCI patients and hypothesized to predict progression in early-stage MCI patients were selected. Cognitive (long-delay free recall, regional primacy score), imaging (hippocampal and entorhinal cortex volumes, fornix fractional anisotropy), and CSF (Aβ1-42/t-tau, Aβ1-42) variables from 36 MCI patients were analyzed with Cox regression and mixed-effect models to determine their individual and combined abilities to predict time to conversion to AD dementia and course of global cognitive functioning, respectively. Results: Those variables hypothesized to predict the course of early-stage MCI patients were most predictive for MCI progression. Specifically, regional primacy score (a measure of word-list position learning) most consistently predicted conversion to AD dementia and course of cognitive functioning. Both the prediction of conversion and course of cognitive functioning were maximized by including CSF Aβ1-42 and fornix integrity biomarkers, respectively, indicating the complementary information carried by cognitive variables and biomarkers. Conclusion: Predictors of MCI progression need to be interpreted in light of the characteristics of the respective MCI sample. Future studies should aim to compare predictive strengths of markers between early-stage and late-stage MCI patients.
Pages 635-647
Christiane Möller, Nikki Dieleman, Wiesje M. van der Flier, Adriaan Versteeg, Yolande Pijnenburg, Philip Scheltens, Frederik Barkhof, Hugo Vrenken (Handling Associate Editor: Josephine Barnes)
More Atrophy of Deep Gray Matter Structures in Frontotemporal Dementia Compared to Alzheimer’s Disease
Abstract: Background: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. Objective: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer’s disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. Methods: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1-weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Results: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Conclusion: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD.
Pages 649-660
Francesca Mangialasche, Mauro Baglioni, Roberta Cecchetti, Miia Kivipelto, Carmelinda Ruggiero, Danilo Piobbico, Lothar Kussmaul, Roberto Monastero, Stefano Brancorsini, Patrizia Mecocci (Handling Associate Editor: Domenico Pratico)
Lymphocytic Mitochondrial Aconitase Activity is Reduced in Alzheimer’s Disease and Mild Cognitive Impairment
Abstract: Background: Specific mechanisms behind the role of oxidative/nitrosative stress and mitochondrial dysfunction in Alzheimer’s disease (AD) pathogenesis remain elusive. Mitochondrial aconitase (ACO2) is a Krebs cycle enzyme sensitive to free radical-mediated damage. Objective: We assessed activity and expression of ACO2 extracted from blood lymphocytes of subjects with AD, mild cognitive impairment (MCI), older adults with normal cognition (OCN, age ≥ 65 years), and younger adults with normal cognition (YCN, age< 65 years). Plasma levels and activities of antioxidants were also measured. Methods: Blood samples were collected from 28 subjects with AD, 22 with MCI, 21 OCN, and 19 YCN. ACO2 activity was evaluated in a subsample before and after in vitro exposure to free radicals. Results: ACO2 activity was significantly lower in AD and MCI cases than controls: ACO2 median activity was 0.64±0.21 U/mg protein for AD, 0.93±0.28 U/mg protein for MCI, 1.17±0.78 U/mg protein for OCN subjects, and 1.23±0.43 U/mg protein for YCN individuals. In subjects with AD and MCI, ACO2 expression was lower than OCN subjects, and ACO2 activity correlated with vitamin E plasma levels (rho: 0.64, p<0.001) and Mini-Mental State Examination total score (rho: 0.82, p<0.001). Furthermore, free radicals exposure reduced ACO2 activity more in individuals with AD than in OCN subjects. Conclusion: Our results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with AD and MCI and correlates with antioxidant protection. Further studies are warranted to verify the role of ACO2 in AD pathogenesis and its importance as a marker of AD progression.
Pages 661-673
Hee Kyung Park*, Seong Hye Choi*, Sun A. Park, Hwa Jung Kim, Yunwhan Lee, Seol-Heui Han, Eun-Joo Kim, Beoung-Chae Kim, Hyun Jeoung Han, So Young Moon, Dong Won Yang, Kyung Won Park, Kee Hyung Park, Bora Yoon, Sang Won Seo, Duk L. Na, Hae Ri Na, Jae-Hong Lee (Handling Associate Editor: Thomas Benke) *These authors contributed equally to this work.
Cognitive Profiles and Neuropsychiatric Symptoms in Korean Early-Onset Alzheimer’s Disease Patients: A CREDOS Study
Abstract: Background & Objective: Early-onset Alzheimer’s disease (EOAD, onset age <65 years) may differ from late-onset Alzheimer’s disease (LOAD) in terms of cognitive profiles and neuropsychiatric symptoms. There have been few studies for Korean EOAD patients using well-structured databases. Previous studies focusing on cognitive profiles between the two groups had a variety of demographic data and comparability. The purpose of this study was to identify the unique profiles of cognitive functions and neuropsychiatric symptoms in Korean EOAD patients that differentiate from LOAD. Methods: Through propensity score matching, a total of 435 patients with EOAD and a total of 435 patients with LOAD were included in this nationwide, multicenter, hospital-based study. Each patient underwent comprehensive neurological examination, interview for caregiver, neuropsychological tests, and brain magnetic resonance imaging. Results: Neuropsychological test results showed worse performances on frontal/executive functions, visuospatial function, and visual memory in EOAD patients as compared to LOAD patients. In terms of neuropsychiatric symptoms, apathy was more common in EOAD patients, while delusions were more prevalent in LOAD patients. The differences in neuropsychiatric symptoms between the two groups were most pronounced in patients with the APOE ɛ4 allele, suggesting that neuropsychiatric symptoms in AD may be influenced by the APOE genotype. Conclusion: Our results suggested that EOAD may be an important phenotype, fronto-parietal dysfunction, in the spectrum of AD, and this finding can provide for early diagnosis of EOAD patients.
Pages 675-685
Alexandra König, Carlos Fernando Crispim Junior, Alexandre Derreumaux, Gregory Bensadoun, Pierre-David Petit, François Bremond, Renaud David, Frans Verhey, Pauline Aalten, Philippe Robert
Validation of an Automatic Video Monitoring System for the Detection of Instrumental Activities of Daily Living in Dementia Patients
Abstract: Over the last few years, the use of new technologies for the support of elderly people and in particular dementia patients received increasing interest. We investigated the use of a video monitoring system for automatic event recognition for the assessment of instrumental activities of daily living (IADL) in dementia patients. Participants (19 healthy subjects (HC) and 19 mild cognitive impairment (MCI) patients) had to carry out a standardized scenario consisting of several IADLs such as making a phone call while they were recorded by 2D video cameras. After the recording session, data was processed by a platform of video signal analysis in order to extract kinematic parameters detecting activities undertaken by the participant. We compared our automated activity quality prediction as well as cognitive health prediction with direct observation annotation and neuropsychological assessment scores. With a sensitivity of 85.31% and a precision of 75.90%, the overall activities were correctly automatically detected. Activity frequency differed significantly between MCI and HC participants (p < 0.05). In all activities, differences in the execution time could be identified in the manually and automatically extracted data. We obtained statistically significant correlations between manually as automatically extracted parameters and neuropsychological test scores (p < 0.05). However, no significant differences were found between the groups according to the IADL scale. The results suggest that it is possible to assess IADL functioning with the help of an automatic video monitoring system and that even based on the extracted data, significant group differences can be obtained.
Pages 687-693
Ramit Ravona-Springer, Salo Haratz, David Tanne, James Schmeidler, Shai Efrati, Clive Rosendorff, Michal Schnaider Beeri*, Jeremy M Silverman* *These authors contributed equally to this work.
Arterial Wall Function is Associated with Cognitive Performance Primarily in Elderly with Type 2 Diabetes
Abstract: Regression analyses compared 41 type 2 diabetes (T2D) and 131 non-T2D cognitively normal elderly males on the associations of arterial wall function measures [large artery elasticity index (LAEI), small artery elasticity index (SAEI), systemic vascular resistance (SVR), and total vascular impedance (TVI)] with cognitive performance (memory, language, and executive functions), controlling for socio-demographic and cardiovascular factors. Higher LAEI and lower TVI were significantly associated with better executive functions performance in T2D but not in non-T2D subjects. Lower TVI was more associated with better language performance in T2D. Results suggest that arterial wall function is associated with cognition in T2D.
Pages 695-704
Ignacio Casado Naranjo, Juan Carlos Portilla Cuenca, Beatriz Duque de San Juan, Alfonso Falcón García, Raúl Romero Sevilla, Ana Serrano Cabrera, Carmen Cámara Hijón, Silvia Romero Chala, José Manuel Fuentes, José María Ramírez Moreno
Association of Vascular Factors and Amnestic Mild Cognitive Impairment: A Comprehensive Approach
Abstract: Background and objective: Current evidence shows that numerous classic vascular risk factors (VRF) contribute to mild cognitive impairment (MCI), but the effects of emerging VRFs are less well-known. Using a comprehensive approach, we assessed the frequency and strength of association between MCI and classic VRFs, subclinical markers of atherosclerosis (cystatin C, lipoprotein(a), high-sensitivity C-reactive protein, and intima-media thickness) and white matter hyperintensities (WMH). Methods: In this case-control study of consecutive MCI patients and cognitively normal controls, subjects underwent clinical and neuropsychological examinations, laboratory analyses, a carotid duplex scan, and a brain magnetic resonance imaging scan. Results: The study included 105 patients with amnestic MCI (aMCI): 24 with single domain amnestic MCI, 81 with multiple domain amnestic MCI, and 76 controls. Compared to controls, patients with aMCI were significantly older and had higher rates of arterial hypertension, atrial fibrillation, and depression. They also had a larger intima-media thickness and higher load of WMHs, both periventricular (WMHpv) and subcortical (WMHsc). In the adjusted analysis, all variables except WMHsc displayed a significant association with aMCI. Body mass index exerted a protective effect. Conclusions: Our findings suggest a direct association between aMCI and age, hypertension, atrial fibrillation depression, intima-media thickness, and WMHpv. Body mass index has a protective effect on this MCI subtype.
Pages 705-720
Claude M. Wischik, Roger T. Staff, Damon J. Wischik, Peter Bentham, Alison D. Murray, John M.D. Storey, Karin A. Kook, Charles R. Harrington
Tau Aggregation Inhibitor Therapy: An Exploratory Phase 2 Study in Mild or Moderate Alzheimer’s Disease
Abstract: Background: As tau aggregation pathology correlates with clinical dementia in Alzheimer’s disease (AD), a tau aggregation inhibitor (TAI) could have therapeutic utility. Methylthioninium (MT) acts as a selective TAI in vitro and reduces tau pathology in transgenic mouse models. Objective: To determine the minimum safe and effective dose of MT required to prevent disease progression on clinical and functional molecular imaging outcomes. Methods: An exploratory double-blind, randomized, placebo-controlled, dose-finding trial of MT (69, 138, and 228 mg /day) was conducted in 321 mild/moderate AD subjects. The primary outcome was change on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity. Effect of treatment on regional cerebral blood flow decline was determined in a sub-study in 135 subjects. After 24 weeks, subjects were re-consented to enter sequential 6- and 12-month blinded extension phases. Registered with ClinicalTrials.gov (NCT00515333). Results: At 24 weeks, there were significant treatment benefits in two independent populations at the 138 mg/day dose: in moderate subjects on the ADAS-cog scale (treatment effect: -5.42 units, corrected p = 0.047) and two other clinical scales; in mild subjects on the more sensitive regional cerebral blood flow measure (treatment effect: 1.97%, corrected p < 0.001). With continued treatment for 50 weeks, benefit was seen on the ADAS-cog scale in both mild and moderate subjects. The delivery of the highest dose was impaired due to dose-dependent dissolution and absorption limitations. Conclusion: The minimum safe and effective daily MT dose is 138 mg and suggests that further study of MT is warranted in AD.
